Pharmacy Law:
Medical Marijuana

Pharmacy
Program/ACPE #: 380-000-06-012-H03
This program furnishes 1.5 hours of credit (0.15 CEU).

Publication Date: May 1, 2006 - Expiration Date: May 1, 2009

Author:

Gerald Gianutsos, PhD, JD
Associate Professor of Pharmacology
University of Connecticut
School of Pharmacy
Storrs, CT

Statements made in this program have not been evaluated by the Food and Drug Administration. Discussion of published or investigational uses of drugs outside of approved labeling is offered for educational purposes only, and the sponsor and publisher of this program do not endorse such off-label use. Nutritional products discussed are not intended for the prevention, diagnosis, treatment, or cure of any disease.

Opening crawl: The motion picture you are about to witness may startle you. It would not have been possible, otherwise, to sufficiently emphasize the frightful toll of the new drug menace which is destroying the youth of America in alarmingly increasing numbers. Marihuana is that drug—a violent narcotic—an unspeakable scourge—The Real Public Enemy Number One!

                                                                                                              Reefer Madness (1936)

INTRODUCTION

Few biologically active substances have generated as much controversy as the plant Cannabis sativa, commonly known as marijuana. Marijuana contains a number of active components, some of which are psychoactive, and is generally regarded as a drug of abuse. However, many of the plant’s constituents have other notable pharmacological properties and have been promoted as possible sources for effective therapeutic agents to treat a broad range of disease states. Pharmacists are aware of the growing popularity of alternative medicines, and efforts to legalize marijuana for medical purposes have been ongoing for more than 30 years. These efforts have been successful in several states, although not without controversy.

A recent US Supreme Court decision has further clouded the medical marijuana issue by highlighting the conflict between federal drug control and state efforts to improve access to the drug. In this article, the proposed medical uses of marijuana and the efforts directed towards its legalization or decriminalization will be reviewed.

PHARMACOLOGY

History
Cannabis sativa was one of the first plants to be used by man in both medicine and religious rites.¹ The plant is also an important source of fiber and hemp-woven fabrics are believed to trace back to 7000 BC.² References to the plant can be found in Assyrian records, Egyptian hieroglyphics, and ancient Greek and Roman medical treatises. Some references date back 5000 years. Dioscorides and Galen found the juice from seeds to be analgesic,¹ an effect that is actively being re-evaluated in this century.

In ancient China, Cannabis was used with other herbs for rheumatic and other painful conditions, disorders of the female reproductive tract and was used in wine as a general anesthetic. A first century manuscript from Syria recommended extracts for painful teeth. In India, marijuana became an integral part of Hindu culture to obtain a sense of well-being, while in China it was used to make cloth and as a medicine.³

Marco Polo, the 13th Century Venetian traveler, returned to Europe with his own tale of cannabis, which in the potent form of hashish, was said to be used as an intoxicant by Hasan-I-Sabbah to send his ruthless followers on missions of murder. There is a belief that the word "assassin" may be derived from the word "hashish," or from Hasan.³ In France, Napoleon’s soldiers returning from Egypt heightened interest in marijuana.

Hemp was introduced into North America in the early 1600s as a fiber² and became a major commercial crop in the South. Extracts of local hemp were also used to treat neuralgia, headaches, asthma, vomiting, and as an oxytocic. A treatise written in 1839 by W.B. O’Shaughnessy, an Irish physician serving in the British Army in India, introduced Cannabis into Western medicine.¹ O’Shaughnessy administered Cannabis to patients with seizures and tetanus and reported on its antiemetic, anticonvulsive, antianxiety and analgesic properties. It also gained popularity as an aphrodisiac.² Marijuana was listed in the United States Pharmacopeia from 1850 until 1942.

In the early part of the 20th Century, the drug began to acquire its notorious reputation purportedly being linked to violence, promiscuity and moral decline.² Its popularity increased in the early 1900s, as American soldiers fighting in Mexico and Panama, and Mexican immigrants in the Southwest, brought the drug across the border.³ Its association with society’s perceived decadence of Black jazz musicians and the attention given to it as a "gateway" drug to other drugs of abuse led to the regulation of marijuana in the United States in 1937. Despite these concerns, interest in marijuana as a medicinal product continues.

Cannabis Compounds
The active constituents found in the Cannabis plant are obtained from the resin secreted by the flowering tops and leaves. Much lower quantities are found in the stems and roots and none in the seeds.⁴ Over 400 chemicals can be found in the marijuana plant, including more than 60 cannabinoids (21-carbon terpenophenols). Many of the cannabinoids are metabolic precursors and degradation products of other cannabinoids.⁵ The amounts of cannabinoids and their relative abundance in a marijuana plant vary with growing conditions, including humidity, temperature, and soil nutrients.

The first major constituent of the plant, delta⁹-tetrahydro cannabinol (THC; originally designated delta¹) was isolated in pure form and its structure elucidated in 1964. Delta⁹-THC and the closely related, but less potent, delta⁸ THC are believed to be the principal psychotomimetic compounds found in the plant. Delta⁹-THC is stereoselective with the (-) trans isomer showing greater activity. A nonpsychotomimetic naturally occurring compound, cannabidiol, has also been isolated.⁶

A number of synthetic substances have recently been synthesized with cannabinomimetic activity, representing a variety of chemical classes.^{7, 8} These drugs represent potentially novel therapeutic agents for the broad range of disease states for which marijuana has been said to have activity.

Receptors and Mechanisms
The mechanism of action of the cannabinoids was a subject of conjecture for many years. Originally, these substances were believed to work by a non-specific disruptive effect on the cell membrane related to their highly lipophilic nature, similar to the general anesthetics.⁸ A selective binding site was identified almost 20 years ago⁹ that mediates the pharmacologic effects of the active constituents of marijuana and related synthetic compounds.

Cannabinoid receptors.—The cannabinoid receptor exists in at least two different subtypes, designated CB₁ and CB₂, and is a member of the large family of G-protein coupled receptors. The CB₁ receptor is localized to brain regions critical for neurological and psychological functions. This receptor may also exist as multiple subtypes. The CB₂ receptor is found preferentially in the periphery, especially in the immune system, and may be involved in the process of inflammation.

Some CB₁ receptors are present on nerve terminals, where they inhibit transmitter release when activated by agonists. Less is known about the physiological roles of CB₂ receptors, which most likely include modulation of cytokine release from immune cells. Some pharmacological evidence supports the existence of additional types or subtypes of the cannabinoid receptor.⁷ The non-psychotomimetic analog, cannabidiol, may act on an as yet unidentified subtype.⁶

Endocannabinoids.—Endogenous ligands to the CB receptors have been identified.¹⁰ Termed endocannabinoids, they provide support for a physiological role for cannabinoids and help to clarify the pharmacological and clinical activity of marijuana. Endocannabinoids are novel targets for potential therapeutic agents.¹¹

The first identified ligand is anandamide (arachidonyl-ethanolamine), an unsaturated fatty acid derived from arachidonic acid, which is synthesized and secreted by nerve and immune cells. Anandamide has a slightly higher preference for CB₁ receptors.¹² Anandamide also binds to the vanilloid receptor (VR1 also known as the TRPV1 receptor), a cation channel expressed by afferent nociceptive (pain sensing) neurons that is also activated by capsaicin.¹² Anandamide is found in high concentrations in regions of the brain regulating functions such as mood, behavior, cognition, movement, and pain and is also found in the spleen and heart.⁵ Anandamide is synthesized from a phospholipid precursor.¹¹ Unlike traditional neurotransmitters, anandamide is not stored in cells but synthesized “on demand.” It is rapidly metabolized by the enzyme fatty acid amide hydrolase (FAAH). Cyclooxygenase-2 and lipoxygenases may also break down anandamide; there is evidence suggesting that the NSAIDs indomethacin and flurbiprofen may act through a cannabinoid mechanism.¹¹ There is also a neuronal uptake mechanism for deactivating anandamide.

A second endocannabinoid, 2-arachidonoylglycerol (2-AG) has also been isolated. 2-AG also acts on CB₁ receptors and is more abundant in the CNS than anandamide but is less potent.⁵ Like anandamide, 2-AG is inactivated by FAAH.

Another potential endogenous substance, palmitoylethanolamine (PEA) has also been investigated, but its role is less well established. PEA has been proposed as a possible selective CB₂ agonist, however, it has also been reported to be an indirectly acting substance capable of inhibiting FAAH and/or enhancing the stimulation of vanilloid receptors by anandamide.¹²

Recently, a unique endocannabinoid, virodhamine, has been identified.¹³ This substance is highly expressed in the CNS. Virodhamine is a full agonist at the CB₂ receptor and a partial agonist of CB₁ receptors.

Pharmacological Effects
Central nervous system.—Most well recognized effects of marijuana are on the central nervous system. Marijuana produces dose-dependent and diverse subjective effects.^{4, 5} Characteristically, smoking the drug results in a state of intoxication with euphoria and relaxation, followed by drowsiness and sedation. Simple motor tasks and complex psychomotor and cognitive tasks are impaired. Reaction time and eye-hand coordination may also be impaired. Perception of time is also distorted.

In some patients, particularly the elderly or other patients with no history of marijuana use, the psychological effects may be disturbing,⁵ including disorientation, anxiety and paranoia. Marijuana also disrupts short-term memory.^{4, 5}

Pain.—Cannabinoid drugs, and the endogenous cannabinoid anandamide, are effective analgesics in animal models of pain.⁵ Endogenous cannabinoids and the CB₁ receptor can be found at different levels of pain pathways and may also modulate inflammation.

Cardiovascular.—THC can produce tachycardia, hypotension and decreased platelet aggregation.⁴ The hypotensive effect appears to be due to a centrally mediated reduction of sympathetic tone involving CB₁ receptors.

Immune system.—Both CB₁ and CB₂ receptors are found on immune cells. Cannabinoids modulate the production of cytokines that are important in immune function and inflammation, increasing some immune responses and decreasing others.⁵ Effects of chronic low-dose exposure on resistance to infection are poorly documented.

Potential Clinical Uses
Advocates for the use of medical marijuana have proposed the use of the drug in a broad range of medical conditions, and some of these potential therapeutic uses have been acknowledged by states with medical marijuana laws. In an exhaustive review of the science base, the Institute of Medicine concluded that marijuana has potential therapeutic value for pain relief, control of nausea and vomiting, and appetite stimulation.⁵

Anti-emetic.—Controlled clinical trials suggesting that marijuana constituents may be useful in reducing nausea in patients receiving cancer chemotherapy were first reported more than 30 years ago.¹⁴ Marijuana analogs are available to treat nausea and vomiting and Cannabis is recommended by oncologists to patients undergoing cancer chemotherapy.⁶

Early studies comparing THC to prochlorperazine showed promising results. In one carefully controlled, double-blind study, THC was compared with metoclopramide for control of cisplatin-induced vomiting.¹⁵ THC reduced the severity of vomiting but was significantly less effective than metoclopramide; complete control of emesis occurred in 47% of those treated with metoclopramide and 13% of those treated with THC. Similar results were noted comparing THC with ondansetron.¹⁶

The most common adverse effects of cannabinoids when used to treat nausea are dry mouth, somnolence, ataxia, dizziness and dysphoria, which are usually transient and tolerable.¹² The non-psychotomimetic analog, cannabidiol, also exerts anti-nausea actrivity.⁶

Anorexia.—Anecdotally, smoking marijuana is often associated with an increase in appetite. Consequently, it has been tested in patients with anorexia due to cancer chemotherapy or AIDS. Dronabinol reportedly improves appetite and stabilizes body weight in AIDS patients.¹² Efficacy in anorexia nervosa has not been observed.⁵ Interestingly, the endogenous cannabinoid, anandamide, and CB₁ receptors have been found in the hypothalamus, an important site for appetite regulation.

Pain.—Animal models have supported the potential analgesic effect of cannabinoids and an endogenous anandamide-mediated analgesic system has been reported.¹⁷ A review of clinical trials on the use of cannabinoids in the management of pain concluded that cannabinoids were more effective than placebo and comparable to codeine.¹⁸ The authors reported numerous adverse effects including dizziness, ataxia, blurred vision, and muscle twitching and concluded that they should not be used in acute postoperative pain. However, the most encouraging effects have been seen in chronic pain associated with cancer.⁵ Marijuana also reduces neuropathic pain in animal models.⁵

CB₁ receptors are found on peripheral pain sensory nerve fibers, while CB₂ receptors modulate inflammation, suggesting multiple analgesic mechanisms. Synthetic analogs of THC with limited CNS access have the potential to be useful as analgesic agents without significant psychotomimetic activity due to effects on peripheral pain mechanisms and inflammation.¹⁹

Muscle spasms.—Cannabinoids are abundant in brain regions that control movement. Many patients with multiple sclerosis (MS) anecdotally report improvement in spasticity, tremor and pain when smoking marijuana. Recent clinical studies in patients with MS have shown mixed results,²⁰ with improvements in spasticity being reported. Positive effects have also been reported in spinal cord injury⁵ and in Parkinson’s disease.¹² A possible cytoprotective effect has been suggested, with cannabinoids possibly modifying both excitotoxicity and immune function in disease models.

Neuroprotection.—Studies suggest that anandamide and other endocannabinoids may be endogenous neuroprotective agents released following tissue damage and may have a potential protective effect in disorders including stroke, Parkinson’s disease, and cerebral trauma.²¹ The significance of these findings is controversial, however. In animal models of neurotoxic insult and neuroinflammation, the modulation of endocannabinoids has shown both a neuroprotective and worsening effect.¹¹ THC is also reported to have antioxidant activity.⁵

Glaucoma.—Smoking marijuana produces a moderate but transient lowering of intraocular pressure with no evidence of a beneficial effect on disease progression or visual acuity.⁵ Marijuana is effective after oral, inhaled or intravenous use but not when applied topically. It has a short (3-4 hour) duration of action. There is no general agreement that it is a therapeutically appropriate option due to the high and frequent doses needed with the accompanying risks. Marijuana has also been tested in treating blepharospasm.

Other.—THC has anticonvulsant activity in animal models,¹² but clinical efficacy in epilepsy is lacking.⁵ Cannabidiol had been reported to have anticonvulsive properties, but these effects may not be mediated by the CB receptor.⁶

Pharmacokinetics
Cannabinoid metabolism is extensive with at least 80 metabolites formed.²² Most of the metabolites appear to be biologically inactive; 11-hydroxy-THC is the primary active THC metabolite. THC enters the enterohepatic circulation and undergoes hydroxylation and oxidation to 11-nor-9-carboxy-delta-9-THC. The glucuronide is excreted as the major urine metabolite along with about 18 nonconjugated metabolites. Both frequent and infrequent marijuana users metabolize THC similarly.²²

Plasma clearance of THC is quite high, (approximately 950 mL/min or greater), however, the rapid disappearance of THC from blood is largely due to tissue redistribution or distribution into fat rather than simply rapid cannabinoid metabolism.²² Metabolism of inhaled marijuana in most tissues is relatively slow or absent. Slow release of THC and other cannabinoids from tissues and subsequent metabolism makes for a very long elimination half-life. The terminal half-life of THC is estimated to be as long as 10-13 days. Some inactive carboxy metabolites have terminal half-lives of 50 hours to 6 days or more and thus serve as long persistence markers for urine testing of prior marijuana use.

The onset of psychoactive and other pharmacologic effects of marijuana is rapid after smoking but much slower after oral doses. When marijuana is smoked, THC in the inhaled smoke is absorbed as an aerosol within seconds and delivered to the brain rapidly and efficiently as would be expected of a very lipid-soluble drug.²² Peak blood levels appear 10-30 minutes after smoking, although the formation of active metabolites may prolong both the peak onset and duration of psychological effects.

When Cannabis is ingested, the onset of action is delayed and variable with subjective effects lasting for 5-12 hours. Peak effects are produced within 1 hour in some subjects while in others the peak is delayed for 4-6 hours.¹² Oral bioavailability of THC, whether given in the pure form or as THC in marijuana, is low and extremely variable, ranging between 5% and 20%.²² Variability can occur even when the same individual is repeatedly dosed under controlled and ideal conditions. Oral THC is subject to first-pass metabolism and erratic absorption from the stomach and bowel, which reduces its bioavailability. After oral doses, the formation of the active THC metabolite, 11-hydroxy-THC, may exceed that of delta⁹-THC and thus contribute to the pharmacologic effects of oral THC or marijuana.²² Relatively little 11-hydroxy-THC is formed after smoking.

The absorbed dose from smoked marijuana varies greatly among individuals.^{12, 23} Among the factors accounting for the variability are loss of active ingredient in side stream smoke, individual variation in puff rate and depth, pyrolysis, and metabolism in the lung. Experienced users are better able to regulate the amount of THC delivered to the lung.²³ This is a factor noted by advocates of medical marijuana who endorse smoking as a superior delivery system compared to oral dosing with government supplied synthetic THC, since the patient who smokes has better control over the dosing. Advocates also note that a smoked form of delivery provides superiority over an oral form when used to treat vomiting.

While smoked marijuana may provide improved control over bioavailability, smoke delivers a variable mixture of THC, other cannabinoids and other biologically active and toxic substances to the lung.⁵ Other possible dosage forms have been proposed including aerosols, lozenges, patches and suppositories.

Tolerance/Dependence
Chronic administration of cannabinoids to animals results in tolerance to many of the acute effects of THC, including memory disruption, decreased locomotion, hypothermia, and analgesia. Tolerance also develops to the cardiovascular and psychological effects of THC and marijuana in humans.⁵ After repeated smoked or oral marijuana doses, marked tolerance is rapidly acquired (after a day or two) to many marijuana effects. After exposure is stopped, tolerance is lost with similar rapidity.²³ Tolerance to cannabinoids appears to result from both pharmacokinetic and pharmacodynamic changes. Chronic treatment with the cannabinoid agonist, CP 55,940, increases the activity of the microsomal cytochrome P450 oxidative system, and chronic cannabinoid treatment produces changes in brain cannabinoid receptors and cannabinoid receptor mRNA concentrations.⁵

Symptoms of marijuana withdrawal include restlessness, irritability, mild agitation, insomnia, sleep EEG disturbance, nausea, and cramping, although the changes were relatively mild.⁵ Withdrawal symptoms have been observed in carefully controlled laboratory studies of people after use of both oral THC and smoked marijuana. In one study, subjects were given very high doses of oral THC: 180-210 mg per day for 10-20 days, roughly equivalent to smoking 9-10 2% THC cigarettes per day. During the abstinence period at the end of the study, the study subjects were irritable and showed insomnia, runny nose, sweating, and decreased appetite. The withdrawal symptoms, however, were short lived and abated after 4 days. There are reports that long-term marijuana use in heavy marijuana users may result in apathy, social isolation, irritability, paranoia and impaired cognition and educational performance.⁵

Marijuana is the third most commonly abused substance, following alcohol and tobacco, with the first use of marijuana most commonly occurring during adolescence.⁵ Many marijuana users progress to the use of other drugs of abuse and opponents of decriminalization of marijuana consider it to be a “gateway” drug. While many drug users have used marijuana as their first experience with an illegal drug, most drug users do not begin their drug use with marijuana but rather with alcohol or nicotine, usually when they are too young to do so legally.⁵

Other Adverse Effects
Smoking marijuana delivers many toxic substances to the lung including many of the chemicals found in tobacco smoke. Given a cigarette of comparable weight, as much as four times the amount of tar can be deposited in the lungs of marijuana smokers as in the lungs of tobacco smokers.⁵ Marijuana smokers have exhibited abnormalities of cells lining the respiratory tract and have an increased risk of lung cancer.⁵ Immunosuppression may also result from marijuana use. Limited reports in humans suggest that marijuana may decrease the secretion of luteinizing hormone (LH) and could interfere with early pregnancy.⁵

LEGAL STATUS

History
Early drafts of the first federal anti-narcotic legislation, the Harrison Act of 1914, sought to include marijuana with other drugs of abuse such as cocaine and heroin.²⁴ The Harrison Act controlled drugs by instituting a tax on their use and violators were prosecuted by the Department of Treasury. The Act also discouraged the treatment of addicts. However, marijuana was not considered to be a problem of major significance and federal regulation of marijuana did not occur until 1937 with the passage of the Marijuana Tax Act, which required anyone producing, distributing, or using marijuana for medical purposes to register and pay a tax. Marijuana prohibition was a major emphasis of the director of the fledgling Bureau of Narcotics and the 1937 Act was passed despite the opposition by the American Medical Association.²⁵

Earlier prohibitions of marijuana occurred at the State level. Utah was the first to outlaw the use of marijuana in 1910, apparently by incorporating restrictions proposed by the Mormon Church. Twenty-six other states followed by 1937. Most of these were Rocky Mountain and southwestern states, which some historians believe was targeted against the drug’s use by Mexican-Americans, and in northeastern states which some believe were motivated by drug use by African-American entertainers and the potential for substitution by abusers of other drugs who were denied access by the Harrison Act and by Prohibition.^24,25

The modern system for regulating drugs of abuse arrived with the passage of the Comprehensive Drug Abuse Prevention and Control Act in 1970. It replaced previous laws and categorized drugs into schedules based on abuse and addiction potential and their therapeutic value. The marijuana plant and THC and other plant constituents are currently regulated as Schedule I controlled substances by the DEA. A drug is placed in Schedule I if it has a high potential for abuse, has no accepted medical use, and lacks accepted safety for use under medical supervision. Medical marijuana advocates (see below) have questioned its categorization as a Schedule I substance based upon these criteria. Schedule I drugs may not be prescribed for any reason. Marijuana arrests reached a record high in 2004 (NOTE: In 2004, 44.2% of the 1,745,712 total arrests in the United States for drug abuse violations were for marijuana—a total of 771,605. Of those, 684,319 people were arrested for possession alone.) An exception to this general regulation of marijuana-like drugs is dronabinol (a synthetic, oral THC), which is a Schedule III drug (see below).

Supporters of the legalization of marijuana filed suit in 1972 to reschedule marijuana to Schedule V.²⁶ The suit, brought by the group NORML (The National Organization for the Reform of Marijuana Laws), argued that marijuana is therapeutic in numerous serious ailments, less toxic, and in many cases more effective than conventional medicines. In 1988, a DEA Administrative Law Judge ruled that marijuana did not meet the legal criteria of a Schedule I prohibited drug and should be reclassified as a Schedule II drug. The DEA Administrator rejected this determination, and this was affirmed by the DC Court of Appeals in 1994. Following failure at the federal level, efforts at decriminalization shifted to the individual states.

On another front, the federal government was forced to allow certain patients access to medical marijuana in 1978 after a "medical necessity" defense was recognized by some courts, creating the Investigational New Drug (IND) compassionate access program.²⁶ The program, which allowed a small number of patients to receive medical marijuana from the government, did not strictly adhere to FDA’s criteria for compassionate use; it was closed to new patients in 1992 after it was flooded by applications from AIDS patients and resistance from government officials who felt that it undercut the federal opposition to the use of illegal drugs.²⁷ The release of synthetic THC (dronabinol) in capsule form in 1985 was also due, in part, to political pressure.

Legally Available Products
Although the Cannabis plant and any products obtained from the plant are Schedule I substances, some products derived from or related to marijuana can be legally obtained by prescription.

Dronabinol.—Dronabinol (Marinol) is a synthetic form of delta⁹-THC available as an oral dosage form. The THC is formulated in sesame oil and marketed as a soft gelatin capsule containing 2.5, 5, or 10 mg of active ingredient. It is used in prophylaxis of nausea in patients receiving cancer chemotherapy. It can also stimulate appetite and has been used in patients with acquired immunodeficiency syndrome (AIDS) and anorexia. The usual dosage is 5 mg/m² given 1-3 hours before chemotherapy and then every 2-4 hours afterward for a total of four to six doses. For other indications, the usual starting dose is 2.5 mg before lunch and supper. The dose may be increased to a maximum of 20 mg/day, administered in divided oral doses. It is currently a Schedule III drug.

Clinical trials with dronabinol have reported an increase in appetite but weight gain is less consistently reported and may be due to an increase in body water rather than lean body mass.²³ The effects have not consistently been associated with improved clinical outcome in AIDS patients. Adverse CNS effects (feeling “stoned”) have been reported.

Dronabinol has been shown to be superior to placebo in controlling emesis associated with cancer chemotherapy.²³ Comparisons with other known antiemetic agents have been mixed, but proponents of medical marijuana argue that an oral dosage form would be inferior to a smoked preparation for nausea and vomiting control and that smoked marijuana should be made available. Dronabinol reportedly has a low abuse potential.²⁸

Nabilone.—Nabilone (Cesamet) is a synthetic, substituted cannabinoid originally developed by Lilly. It is available in Canada as a 1 mg capsule and used to treat nausea and vomiting from cancer chemotherapy. It has a duration of action of 8-12 hours. Side effects from nabilone include drowsiness, dizziness, dry mouth, euphoria, and a decrease in blood pressure.²⁹ When compared with standard antiemetic agents (eg, prochlorperazine, metoclopramide), cannabinoids including nabilone and dronabinol were at least as effective with good patient acceptance.³⁰ It appears to be especially effective in children, who experience fewer side effects. Nabilone has also been studied in phase II trials as an agent for lowering intraocular pressure, as an antianxiety agent, and as a drug for producing bronchodilation.²⁹ An application for approval in the United States was denied by the FDA in January 2006 due to labeling concerns, but was subsequently approved in May 2006.

Delta⁹-THC and cannabidiol.—Sativex^® was approved for treatment of neuropathic pain in multiple sclerosis patients in Canada and other regulatory approval is being sought. Sativex is derived from an extract of specifically bred Cannabis varieties and is a mixture of delta⁹-THC and cannabidiol. It differs from other products in that it is an oral/mucosal spray, which allows more flexible dosing; each spray of Sativex delivers a fixed dose of 2.7 mg THC and 2.5 mg CBD.

Synthetic agonists.–—search for synthetic cannabis drugs has been underway for more than 30 years.⁸ In the 1970s, Pfizer launched a cannabinoid research program that resulted in the development of a cannabinoid analog, levonantradol, that was 1000 times more potent than THC.³¹ Clinical trials showed that it was effective for postoperative pain and chemotherapy-associated nausea and vomiting; however, the company discontinued its development because the side effects (sleepiness, dysphoria, dizziness, thought disturbance, and hypotension, among others) were judged to be excessive. Lilly also made a research commitment in the early 1970s that led to the development of nabilone (above).

The search for synthetic analogs was reinvigorated following the discovery of selective cannabinoid binding sites and a number of compounds are in development, although none were commercially available at the time this lesson was prepared. A wide variety of chemical classes are being investigated which include CB₁ or CB₂ selective agonists of varying potency, as well as drugs that enhance the effects of endocannabinoids by inhibiting their degradation or uptake.

Rimonabant.—Rimonabant (Acomplia) differs from other cannabinoid-like drugs since it is not an agonist but a selective CB₁ receptor antagonist or inverse agonist. It was originally tested for use in schizophrenia and found to be ineffective.¹⁹ However, other promising uses emerged. Patients taking the drug exhibited weight loss and recent clinical trials have confirmed a loss of body weight in obese patients. This is consistent with a role for anandamide and CB₁ receptors in appetite regulation. As of March 2006, the drug was awaiting approval by FDA. Several lines of evidence suggest that rimonabant may be a novel therapeutic agent for treating the craving associated with a number of drugs of abuse,³² and it is undergoing clinical trials as an aid to reducing alcohol and tobacco consumption.

State Initiatives
Although the use of marijuana for medical purposes is prohibited by Federal Law, a number of states have enacted medical marijuana laws. The laws vary in the individual states with respect to the type of program under which marijuana may be used, the medical conditions for which it may be used, and the source of the marijuana (eg, government source or home-grown).³³

New Mexico became the first state to permit the medical use of marijuana, allowing physicians to supply it to patients suffering from nausea due to chemotherapy in 1978. The law was later modified to comply with federal IND regulations requiring a therapeutic research program and this approach was copied by 21 other states in the late 1970s. Under these programs, physicians could distribute marijuana to patients in a state-approved clinical research trial. Regulatory constraints prompted by federal oversight of the programs caused many of the states to abandon this approach.³³ Marijuana could only be obtained from the National Institute on Drug Abuse (NIDA) and patients were supposed to be assigned to drug or placebo groups under a research protocol. The Cannabis was grown on a farm at the University of Mississippi, the only legal marijuana farm in the United States, and sent to North Carolina, where it was rolled into cigarettes that were supposed to have the same potency as street marijuana (2% THC).²⁷ The marijuana was shipped to a designated pharmacy that had to comply with stringent DEA regulations for drug security. The application process took 4-8 months.²⁷

In the years since, 36 states have enacted laws that recognize the medical use of marijuana (laws in 6 of the states have expired or been repealed, so that 30 currently recognize some form of medical use, although not all the states have laws that are effective).³⁴ Nine of the states enacted laws through ballot initiatives.

In many cases, the laws are ineffective. State laws authorizing physicians to prescribe marijuana are in conflict with federal law, which prohibits such prescriptions since marijuana is a Schedule I substance under the Controlled Substances Act. Moreover, patients may have difficulty obtaining a filled prescription since a pharmacy dispensing marijuana would also be violating federal law. Similar problems exist in states that have taken the approach of reclassifying marijuana in another Schedule; this still conflicts with federal law. Consequently, reluctance by physicians and pharmacists to supply and fill prescriptions renders many of these state laws unworkable. This produces a reliance on the federal government to supply the drug for dispensing.

In response, 11 states had legalized not only the use of marijuana but also its possession and cultivation³⁵ at the time this lesson was prepared. In some states, patient registration and the issuance of identification cards is a component of the law. Some of the examples of the different programs are described below.

California.—As a result of a ballot initiative passed in 1996, California exempts individuals from prosecution if marijuana possession or cultivation is solely for the medical purposes of the patient. The rule exempts both patients and caregivers from prosecution. A patient obtains a written or oral recommendation or approval from a physician who has determined that the patient’s health would benefit from medical marijuana in the treatment of a qualifying condition. A qualifying condition is cancer, anorexia, AIDS, chronic pain, spasticity, glaucoma, arthritis, migraine, or “any other illness for which marijuana provides relief.” Patients in California do not need a prescription to possess marijuana, merely a “recommendation” from a practitioner. [A recommendation has been determined to be legally protected free speech and protects a physician from prosecution.]

California provides a voluntary ID card to patients. The card can assist law enforcement officials in determining whether an individual using marijuana meets the requirements of the state’s Compassionate Use Act. A patient with a state-issued ID card may possess up to 8 ounces of marijuana or 6 mature plants without fear of arrest or prosecution. The ID may be verified via a telephone 800 number. For patients without an ID card, there is no numerical limit, but an amount of “marijuana for the personal medical purposes of the patient” is permissible.

California also provides an implied protection to medical marijuana dispensaries that collectively or cooperatively provide marijuana to patients. It is estimated that there are 100,000 medical marijuana users in California.³⁵ Surveys of medical Cannabis users in California report that the most common users of marijuana are those with HIV, cancer, or pain.⁵

Opponents to the California initiative note that patients do not necessarily need to be evaluated or diagnosed to receive marijuana and once it is recommended, the patient does not need to be reevaluated to assess its effectiveness.³⁶ They also suggest that marijuana cooperatives are operating as a façade to supply the drug to any user regardless of medical use, pointing out that undercover agents have shut down clubs selling to minors, while one user claimed it helped with an ingrown toenail problem.

Voters in Oregon and Washington passed a similar law in 1998. Colorado voters approved an amendment to the state constitution in 2000, which permits registered user to possess up to 2 ounces of marijuana. Patients who do not join the registry or possess greater amounts of marijuana than allowed by law may argue the affirmative defense of medical necessity if they are arrested on marijuana charges. Other states, such as Maine, do not have a registry program.

Hawaii.—In Hawaii, a medical marijuana law was passed in 2000 by the State legislature rather than by a ballot initiative. It thus became the first state legislature to do so. Much like the law in California, the Hawaiian law removes state-level criminal penalties on the use, possession and cultivation of marijuana by patients who possess a signed statement from their physician affirming that he or she suffers from a debilitating condition and that the "potential benefits of medical use of marijuana would likely outweigh the health risks." Patients diagnosed with the following illnesses are afforded legal protection under this act: cachexia; cancer; chronic pain; Crohn's disease; epilepsy and other disorders characterized by seizures; glaucoma; HIV or AIDS; MS and other disorders characterized by muscle spasticity; and nausea. Other conditions may be approved by the Hawaii Department of Health. Patients (or their primary caregivers) may legally possess no more than 1 ounce of usable marijuana, and may cultivate no more than seven marijuana plants, of which no more than three may be mature. The law establishes a mandatory, confidential state-run patient registry that issues identification cards to qualifying patients.

Maryland.—The law in Maryland requires a court to consider a defendant's use of medical marijuana to be a mitigating factor in marijuana-related state prosecution. If the patient, post-arrest, successfully makes the case at trial that his or her use of marijuana is one of medical necessity, then the maximum penalty allowed by law would be a $100 fine.

Iowa.—Iowa has a dual Schedule law. Marijuana is in Schedule I but is considered to be in Schedule II if used for medicinal purposes. The District of Columbia also attempted to place marijuana in Schedule III, but the federal government prevented the law from taking effect.

Recent Federal Developments
The US Supreme Court dealt a blow to the state initiatives in 2005 when it ruled that federal anti-drug laws can be enforced against users of medical marijuana in California and other states. The case, Gonzales v. Raich [125 S. Ct. 2195, 162 L.Ed.2d 1 (2005)], was brought after federal Drug Enforcement Administration agents seized and destroyed cannabis plants being used by patients under the California Compassionate Use Act, which authorizes limited marijuana use for medicinal purposes (see above). The agents claimed enforcement of the federal Controlled Substances Act (CSA), which prohibits the use and possession of marijuana. Ms. Raich was a patient registered under the California Use Act who was severely debilitated. She was using marijuana, claiming relief from pain and wasting and a poor response to opiates. DEA agents seized and destroyed marijuana plants grown by her caregivers. She and another patient brought suit to prohibit the enforcement of the CSA. Essentially, the Supreme Court decided that the federal law pre-empted the state initiative so that the federal agents acted properly.

However, the Court’s ruling did not explicitly invalidate the California act, but the federal government can enforce, if it chooses to, the CSA against Californians (or users in other states) for cultivating and using marijuana on the recommendation of physician.

The Court also left open the possibility that the FDA could be persuaded to place marijuana into a Schedule other than Schedule I. In a footnote, Justice Stevens noted that if the scientific evidence offered by medical marijuana supporters is true, it would "cast serious doubt" on the Schedule I classification.

The effect that the ruling will have on prosecution and on legislative activity remains to be seen. It is noteworthy that in March 2006, an attempt to pass a medical marijuana bill in Massachusetts was essentially killed, citing the Supreme Court decision.

SUMMARY

Marijuana has a long history of medical use. The elucidation of a receptor basis for cannabinoid drugs and the discovery of an endogenous cannabinoid substance provide further evidence for a physiological and therapeutic role for marijuana-like drugs. Many states have recognized the potential therapeutic basis for marijuana and have attempted to decriminalize the medical use of the drug. Pharmacists, however, need to appreciate that these state laws are in conflict with federal law and that efforts to circumvent the federal law may place them in jeopardy. The development of synthetic cannabinoids is in its infancy, but these agents may provide avenues to deliver on the therapeutic promise of marijuana with fewer side effects and fewer legal complications.

1. All of the following references to the medical use of marijuana are true EXCEPT:
a. can be traced back 5000 years
b. are found in ancient Greek medical treatises
c. are found in ancient Roman medical treatises
d. are found in Egyptian hieroglyphics
e. are found in the O.T. books of the Bible

2. In the United States, the cannabis plant:
a. was once a major commercial crop in the South
b. was never recognized for its medical use
c. first gained a reputation as a social problem in the 1970s
d. supplied fiber that was woven into cloth
e. is legal to possess if used for medical purposes

3. The active constituents in marijuana are found primarily in the plant’s:
a. root
b. rhizomes
c. seeds
d. bark
e. flowering tops

4. The primary active ingredient in marijuana is:
a. delta⁹-THC
b. cannabidiol
c. anandamide
d. morphine
e. cyclohexanol

5. An endogenous substance that binds to cannabinoid receptors is:
a. norepinephrine
b. anandamide
c. prostaglandin E₂
d. prostaglandin I₂
e. vanillin

6. The marijuana receptor found in the CNS that is likely responsible for most of the potential uses and side effects of the drug is:
a. CB₁
b. CB₂
c. CB₃
d. VR1
e. VR2

7. In evaluating the antiemetic effects of marijuana, it:
a. was found to have no efficacy
b. showed promising results compared to prochlorperazine
c. was found to be superior to metoclopramide
d. was found to be superior to ondansetron
e. could not be tested for this purpose due to side effects

8. In evaluating the effects of marijuana on pain it:
a. was no better than placebo
b. was found to be roughly equivalent in activity to codeine
c. is useful in acute pain but not in chronic pain
d. has no effect on inflammation
e. stimulated, rather than antagonized, nociceptive neurons

9. Side effects of marijuana when used for medical purposes include all of the following EXCEPT:
a. sedation
b. dizziness
c. dysphoria
d. decreased appetite
e. dry mouth

10. There is evidence for a positive effect of marijuana in glaucoma:
a. when taken orally
b. when applied via eye drops
c. in improving visual acuity
d. with a long duration of action
e. in halting disease progression

11. Smoked marijuana:
a. potentially delivers toxic substances to the lung
b. may provide better control over dosing than orally administered marijuana
c. produces peak blood levels within 10-30 minutes
d. may result in a variable delivered dose
e. all of the above are correct

12. Oral marijuana:
a. produces a faster onset of action than smoked marijuana
b. has a peak onset of action of 15-30 minutes
c. is associated with a higher rate of metabolism than smoked marijuana
d. produces a consistently high blood level of active ingredient
e. is associated with high oral bioavailability

13. Marijuana was first regulated at the federal level by the Marijuana Tax Act, passed in:
a. 1909
b. 1914
c. 1937
d. 1950
e. 1970

14. In which DEA Schedule is marijuana found?
a. Schedule I
b. Schedule II
c. Schedule III
d. Schedule IV
e. Schedule V

15. All of the following statements about Marinol are true EXCEPT it is:
a. a synthetic form of THC
b. a form of marijuana that can be legally prescribed
c. used to relieve nausea and vomiting associated with cancer chemotherapy
d. only taken orally
e. a schedule IV drug

16. All of the following are true statements about rimonabant EXCEPT it:
a. is a CB₁ receptor antagonist
b. produces a reduction in appetite
c. is approved by FDA as a smoking deterrent
d. reduces craving by a number of drugs of abuse
e. is ineffective in treating schizophrenia

17. Lawsuits were brought in the 1970s in attempt to relax the scheduling of marijuana. These were based on:
a. a constitutional right to medical treatment
b. the assertion that marijuana did not fit the legal criteria for the schedule it was placed into
c. the theory that marijuana was not subject to regulation by the FDA
d. a notion that the penalties for possession were too severe
e. the finding that marijuana cold be produced much more cheaply than other drugs

18. If a state permits physicians to prescribe marijuana for medical purposes:
a. pharmacists may dispense marijuana without legal concerns
b. pharmacists need a special state license to dispense marijuana
c. pharmacists are at risk since dispensing it is not permitted by federal law
d. pharmacists can dispense it but only after earning 0.3 CEUs of specialized credit
e. the patient must obtain the drug directly from the physician

19. The only legal marijuana farm in the United States is located in:
a. New Mexico
b. Wisconsin
c. Maine
d. North Carolina
e. Mississippi

20. What did the Supreme Court decide in a 2005 decision about medical marijuana?
a. terminally ill patients are entitled to compassionate use of marijuana
b. marijuana should be placed in a less restrictive Schedule
c. the Federal Controlled Substances Act takes precedence over the California initiative
d. marijuana should be decriminalized
e. the penalty for possession was increased by 400%